Cancer stem cells (CSCs) are a small population of cells with stem cell-like properties found in tumors. CSCs are closely associated with tumor heterogeneity, which influences tumor progress, metastasis, and drug resistance. Here, we propose a concept to enhance efficacy of cancer therapy through CSC reprogramming into non-tumorigenic cells using stem cell -derived exosomes with osteoinductive potential. We hypothesized that exosomes derived from osteogenic differentiating human adipose-derived stem cells (0D-EX0s) contain specific cargos capable of inducing osteogenic differentiation of CSCs. Quantitative RT-PCR analysis revealed that OD-EXO5 enhanced the expression of osteogenic-related genes, such as alkaline phosphatase (ALPL), osteocalcin (BGLAP), and runt-related transcription factor 2 (RUNX2). In addition, expression of drug-resistance genes such as ATP binding cassette (ABC) transporter, the breast cancer gene family (BCRA1 and BCRA2), and the ErbB gene family were significantly decreased in OD-EXO-treated CSCs. Our findings suggest that OD-EXOs function as a biochemical cue for CSC reprogramming and contribute to overcoming therapeutic resistance. (C) 2019 Elsevier Inc. All rights reserved.